We propose to explore animal models of lung disease in a multidisciplinary fashion in order to gain insight into the pathophysiologic, biochemical, immunologic and ultrastructural determinants of the response of the lungs to injury. A number of animal models of diffuse lung disease will be studied: emphysema, interstitial pulmonary fibrosis, hypersensitivity pneumonia, bronchial injury, cadmium injury, non-cardiogenic pulmonary edema, the post-pneumonectomy state, the growing lung and the aging lung. Lung mechanics and gas exchange will be examined. Collagen, elastin, glycosaminoglycan and proteoglycan biochemistry will be evaluated over the course of time. A full range of ultrastructural techniques, including newly-developed methods of staining glycosaminoglycans, proteoglycans and endogenous hydrolases will be employed. Great emphasis will be placed on the study of lung and tracheal organ cultures and of pure cell systems from the lung, fetal and adult fibroblasts, myofibroblasts, alveolar macrophages, the lipid interstitial cell, smooth muscle cells and endothelial cells. A full range of ultrastuctural and biochemical techniques will be focused on purified preparations of alveolar-capillary basement membrane. The place of thyroid hormone on pulmonary integrity will be explored. Factors which control the entry into normal and diseased lungs of polymorphonuclear neutrophils, macrophages and lymphocytes will be identified, purified and their role in inflammation and the fibrotic process will be bioassayed. Intensive explorations of the elastase-antielastase system, including synthetic antielastases, will be carried out, with the aim of developing approaches to the prevention of emphysema. A laboratory devoted to clinical-epidemiological studies will relate clinical, radiographic, physiologic and lung-structure data; ultrastructural, biochemical and immunologic methods will be brought to bear on human material. Thus, basic and clinical studies will be carried on in parallel. It is anticipated that the results of all of these studies will give rise to greater understanding of the processes of normal growth and aging of the lung and the nature of the injuries and their repair, which results in the development of pulmonary emphysema, interstitial pulmonary fibrosis and chronic bronchial injury. We hope that new diagnostic and therapeutic initiatives will derive from these studies.